Breaking News
January 22, 2018 - Mallinckrodt Completes Stannsoporfin New Drug Application Filing
January 22, 2018 - ACOG Backs ‘Cascade Testing’ for Cancer-Related Mutations
January 22, 2018 - The terrible toll tennis can take on top players who play too much
January 22, 2018 - KAIST scientists identify cellular mechanism for severe viral hepatitis
January 22, 2018 - New genomic tools provide better understanding of the human immune system
January 22, 2018 - Improving QoL with an App?
January 22, 2018 - First step toward CRISPR cure of Lou Gehrig’s disease
January 22, 2018 - Scientists uncover the proteins responsible for movement
January 22, 2018 - New clinical practice guideline provides recommendations for use of anticoagulants during heart surgery
January 22, 2018 - Depressive symptoms associated with poorer survival in patients with head and neck cancer
January 22, 2018 - Restaurant Bans Have Big Impact on Smoking Rates
January 22, 2018 - D.C. Week: CMS Outlines Path for Medicaid Work Mandate
January 22, 2018 - Study identifies new loci associated with asthma enriched in epigenetic marks
January 22, 2018 - New bug may reduce misery of hay fever sufferers
January 22, 2018 - Specially prepared supplement helps women to run faster, study shows
January 22, 2018 - 3-D Stent Retriever with Aspiration Proves Mettle in AIS
January 22, 2018 - Public health research seeks to understand how natural disasters impact spread of Zika
January 22, 2018 - Research reveals role of nanophenomenon in stimulating bone-repair process
January 22, 2018 - Drinking during late adolescence could be first step to liver problems in adulthood
January 22, 2018 - Epilepsy associated with volume and thickness differences in brain matter
January 22, 2018 - Trevena Announces FDA Acceptance for Review of New Drug Application for Olinvo (oliceridine) Injection
January 22, 2018 - A Noteworthy Margin of Error
January 22, 2018 - Firm advances human trials of revolutionary vaccine
January 22, 2018 - Many Indians put away treating orthopedic problems
January 22, 2018 - Cherwell releases new pocket guide to prepared culture media
January 22, 2018 - Huron earns ISO 13485 certification for quality management system
January 22, 2018 - Avion Pharmaceuticals Announces FDA Approval of Balcoltra (levonorgestrel and ethinyl estradiol tablets and ferrous bisglycinate tablets) Oral Contraceptive
January 22, 2018 - Multi-Gene Test For Early CVD; Neighborhood HF Risk; Novel Testosterone Drugs
January 22, 2018 - Skipping breakfast disrupts ‘clock genes’ that regulate body weight
January 22, 2018 - Creativity May Rely on ‘Teamwork’ in the Brain
January 22, 2018 - NeuroBreak: Alzheimer’s Germ Contest; High Salt Diet May Be Bad for Brain
January 22, 2018 - Diabetics may often fare poorly in hospice care
January 22, 2018 - Performance enhancing benefits of caffeine more apparent for infrequent tea, coffee drinkers
January 22, 2018 - HHS Unveils Framework for Interoperability
January 22, 2018 - More dentists to discuss risks of HPV-related cancers with their patients
January 21, 2018 - Research shows how Zika virus damages placenta to cause malformations in babies
January 21, 2018 - Achaogen Announces FDA Acceptance of New Drug Application with Priority Review for Plazomicin for Treatment of Complicated Urinary Tract Infections and Bloodstream Infections
January 21, 2018 - Drug Allergies: Time to Re-Test?
January 21, 2018 - Mitochondrial protein in cardiac muscle cells linked to heart failure, study finds
January 21, 2018 - Women more likely than men to die from a heart attack
January 21, 2018 - Next generation genomic sequencing can help detect pathogens after joint replacement
January 21, 2018 - Gov’t Shutdown Looms as Senate Debates Spending Bill
January 21, 2018 - Emergency Readiness for Older Adults and People with Disabilities
January 21, 2018 - Heart health at risk for Latinas over worries about deportation
January 21, 2018 - Scientists methodically identify genes related to blood feeding and non-biting mosquitoes
January 21, 2018 - Researchers discover potential target genes to halt thyroid cancer progression
January 21, 2018 - Youth with shared residency after parents’ divorce have less mental issues
January 21, 2018 - Sleep Better, Lose Weight? – Drugs.com MedNews
January 21, 2018 - More $$ Needed for Health Emergencies, Senators Told
January 21, 2018 - Gene test to predict breast cancer recurrence less cost effective in real world practice
January 21, 2018 - Study finds rise in number of adolescents receiving psychiatric or neurodevelopmental diagnosis
January 21, 2018 - Reminders can improve immunization rates
January 21, 2018 - A More Personalized Approach to PSA Screening in 2017
January 21, 2018 - T-cells engineered to outsmart tumors induce clinical responses in relapsed Hodgkin lymphoma
January 21, 2018 - Tetraphase Pharmaceuticals Announces Submission of New Drug Application to FDA for Eravacycline for the Treatment of Complicated Intra-Abdominal Infections (cIAI)
January 21, 2018 - Have Robotics Had a Detrimental Effect on Surgical Residency?
January 21, 2018 - Being bilingual may help autistic children
January 21, 2018 - Metrics Are Not Widespread in Rheumatoid Care
January 21, 2018 - Neuroanatomic abnormalities ID’d in those at risk for autism
January 21, 2018 - Children born with Down’s syndrome have superior genome that compensates for disability
January 21, 2018 - Study finds higher risks for asymptomatic paroxysmal AF patients
January 21, 2018 - The Second Stage of Diet Resolutions
January 21, 2018 - CT Scans Reduce Lung Cancer Deaths … But Among Whom?
January 21, 2018 - ADHD drug use soars among young women
January 21, 2018 - Researchers propose new regulation mechanism linked to action of SirT6 on chromatin
January 21, 2018 - Statins appear to reduce risk of repeated surgery in patients who undergo vitrectomy
January 21, 2018 - Morning Break: Hep A Outbreak Spreads; Tide Pod Challenge; Keeping Lobsters Out of Hot Water
January 21, 2018 - EULAR and ACR present SLE classification criteria at the 2017 ACR/ARHP Annual Meeting
January 21, 2018 - Progenics Pharmaceuticals Announces FDA Acceptance of New Drug Application for Azedra (iobenguane I 131) in Pheochromocytoma and Paraganglioma
January 21, 2018 - House Passes Funding Bill with 6-Year CHIP Renewal
January 21, 2018 - DASH ranked Best Diet Overall for eighth year in a row by U.S. News and World Report
January 21, 2018 - Dementia study sheds light on how damage spreads through brain
January 20, 2018 - Morning Break: Missing Maria Deaths; N.J. Doc Charged in Wife’s Murder; Viva Vaseline!
January 20, 2018 - No interventions proven to prevent late-life dementia
January 20, 2018 - Judge orders new Olympus trial over superbug death
January 20, 2018 - Don’t Rely on Just One Blood Pressure Test for Kids: Study
January 20, 2018 - Going Off the Deep End About Water
January 20, 2018 - Parental attention can reduce risk of drug abuse in adolescence
January 20, 2018 - Mast Uri System offers efficient and cost-friendly diagnostic solution
January 20, 2018 - International SOS, Chatham House sign partnership agreement to further advance Global Health Security Agenda
New SERM Shows Promise in Advanced Breast Cancer

New SERM Shows Promise in Advanced Breast Cancer

image_pdfDownload PDFimage_print

Action Points

  • In women with estrogen receptor-positive, hormone-refractory metastatic breast cancer, oral Z-endoxifen hydrochloride, the potent metabolite of tamoxifen, provided substantial drug exposure regardless of CYP2D6 genotype, acceptable toxicity, and promising antitumor activity.
  • Note that the study was unable to determine the maximum-tolerated dose of oral endoxifen, and dose escalation was discontinued at 160 mg per day and endoxifen concentrations >1,900 ng/mL.

In women with estrogen receptor-positive, hormone-refractory metastatic breast cancer, oral Z-endoxifen hydrochloride, the potent metabolite of tamoxifen, provided substantial drug exposure regardless of CYP2D6 genotype, acceptable toxicity, and promising antitumor activity, researchers reported.

Results from a phase I study in 38 patients with metastatic breast cancer demonstrated a clinical benefit rate (stable disease ≥ 6 months) of 26.3%. including a partial response by RECIST criteria in three patients who experienced progression during prior tamoxifen therapy, according to Matthew P. Goetz, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues.

Clinical benefit was also seen in seven patients who had no prior tamoxifen treatment or who didn’t experience progression with adjuvant tamoxifen. The median progression-free survival (PFS) time was 110 days, with a 1-year PFS rate of 15%, they wrote online in the Journal of Clinical Oncology.

The study was unable to determine the maximum-tolerated dose of oral endoxifen, and dose escalation was discontinued at 160 mg per day and endoxifen concentrations >1,900 ng/mL. At the time of data lock on March 5, 2017, seven patients had died due to metastatic breast cancer. Of the 31 patients who were alive, two did not have disease progression and 29 did.

Notably, CYP2D6 — the enzyme that converts tamoxifen to endoxifen — was not associated with either Z-endoxifen oral clearance or PFS, the study showed.

Based on these results, “The relationship between CYP2D6 genotype, endoxifen exposure, and the antitumor benefit of both drugs will be evaluated in the randomized phase II trial of Z-endoxifen and tamoxifen,” authors wrote. The trial will directly compare endoxifen (80 mg/day) with tamoxifen (20 mg/day) in women with prior aromatase inhibitor (AI) progression.

For the current study, 41 women were enrolled from March 25, 2011 to Dec. 9, 2014, and 38 were included in the maximum-tolerated dose (MTD) determination. A total of 36 patients experienced progression while on an AI, 21 while on fulvestrant (Faslodex), and 15 progressed on prior tamoxifen therapy.

Patients received 20, 40, 60, 80, 100, 120, or 160 mg of Z-endoxifen by mouth daily or until unable to continue treatment. Dose levels 40, 80, and 100 mg/day were also studied in the expansion phase of the trial. Of the 16 patients enrolled in the expansion cohorts, six were randomized to 40 mg/day, five to 80 mg/day, and five to 100 mg/day.

Dose-limiting toxicities were reported in two patients at the 60-mg dose: a pulmonary embolus after one cycle of treatment and a grade 4 hypertriglyceridemia after five treatment cycles. No eye toxicity was observed and there were no adverse effects reported in the expansion cohorts.

“Long-term studies will be necessary to fully evaluate the adverse effect profile of Z-endoxifen,” the authors said.

Other selective ER modulators (SERMs) have been shown to reduce cholesterol levels and endoxifen appears to do the same. Preliminary results suggest this new SERM reduces both total and LDL cholesterol levels.

Patients with low CYP2D6 enzyme activity exhibit significantly lower endoxifen concentrations when treated with tamoxifen, Goetz’s group pointed out. Data from this study indicate that even non-therapeutic levels of Z-endoxifen can have antitumor activity in patients experiencing progression with tamoxifen, they said.

Patients with prior tamoxifen exposure and a CYP2D6 activity score ≥2.0 generally had rapid clinical progression with a shorter median PFS compared with patients with reduced CYP2D6 metabolism and an activity score ≤1.5 (61 vs 132 days, respectively, P=0.046).

In an accompanying editorial, V. Craig Jordan, PhD, of the MD Anderson Cancer Center in Houston, said that while the value of endoxifen as a salvage therapy will be determined in future clinical studies, “this could just be the beginning of a new era. Perhaps it is the right time to consider improving women’s health with a new SERM.”

More than 30 years ago, Jordan — known as the “Father of Tamoxifen” — discovered that the drug’s anti-estrogenic properties could halt breast cancer growth, thus paving the way for SERMs.

Although AIs are the current standard of care in postmenopausal women with breast cancer, the consequences of long-term therapy remain a concern, he noted.

“Improvements in the use of SERMs may be an important first step in creating an improved quality of life for an aging population,” suggested Jordan, noting that using adjuvant tamoxifen therapy for 10 years makes it possible “to save the lives of 50% of patients with ER-positive breast cancer.”

In addition to potentially reducing risk of breast cancer recurrence, a new SERM might also improve overall health in menopausal women by lowering risk of osteoporosis, coronary heart disease, and stroke without increasing the odds of endometrial cancer, Jordan pointed out.

“It is not just about being alive; it is about being well,” he wrote.

The study was funded by the Mayo Clinic, the Regis Foundation, Prospect Creek Foundation, the George M. Eisenberg Foundation for Chanties, and the National Cancer Institute.

Goetz disclosed relevant relationships with Eli Lilly, bioTheranostics, RNA Diagnostics, Eli Lilly, and Pfizer. Co-authors disclosed multiple relevant relationships with industry.

Jordan disclosed no relevant relationships with industry.

  • Reviewed by
    Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

2017-10-31T09:30:00-0400

Tagged with:

About author

Related Articles